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Published ahead of print on April 24, 2003, doi:10.1165/rcmb.2002-0247OC

Am. J. Respir. Cell Mol. Biol., Volume 29, Number 3, September 2003, 410-418

A more recent version of this article appeared on September 1, 2003
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Submitted on November 20, 2002
Revised on April 23, 2003

Adenosine Receptors and Phosphodiesterase Inhibitors Stimulate Cl- Secretion in Calu-3 Cells

Bryan R Cobb1, Lijuan J Fan2, Timea E Kovacs3, Eric J Sorscher4, and John P Clancy2*

1 Department of Human Genetics, University of Alabama at Birmingham, Birmingham, AL, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA, 2 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA, 3 Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA, 4 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA

* To whom correspondence should be addressed. E-mail: jclancy{at}peds.uab.edu.

We investigated CFTR activation by clinically used phosphodiesterase inhibitors (PDEis) in Calu-3 cell monolayers alone and in combination with A2B adenosine receptor stimulation. This receptor pathway has previously been shown to activate wildtype and mutant CFTR molecules. Several PDEis, including milrinone, cilostazol (Pletal®), papaverine, rolipram, and sildenafil (Viagra®) produced Isc that was glibenclamide sensitive, achieving 20-85% of forskolin-stimulated Isc. Papaverine, cilostazol, and rolipram also augmented both the magnitude and the duration of Isc following low dose stimulation of adenosine receptors with Ado (0.1 to 1.0 µM, p < 0.01). Subsequent studies demonstrated that very low concentrations of cilostazol or papaverine (~1/2 peak serum concentrations) were sufficient to activate Isc, and both agents markedly augmented Ado-stimulated Isc (1 µM, p < 0.01). Our results provide evidence that select PDEis, at concentrations achieved as part of systemic therapies, can activate CFTR-dependent Isc in Calu-3 cell monolayers. These studies also indicate that PDEis have the capacity to augment an endogenous CFTR-activating pathway in an "in vivo"-like model system, and support future investigations of these agents relevant to cystic fibrosis.




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